Prostacyclin (PGI.sub.2) of the following structure is of various pharmacological effects including blood platelet agglutination inhibitory activity and vasodilation activity, and is considered to be promising for development of medicine. However, prostacyclin has such a drawback, on the other hand, that it is a very unstable compound. ##STR1##
Of the prostacyclin derivatives, carbacyclin (called 9(0)-methanoprostacyclin) of the following formula (XVII) has been known to be a chemically stable compound in which the oxygen atom of enol ether moiety of prostacyclin (PGI.sub.2) is substituted with a methylene group. ##STR2##
Processes for the synthesis of an optically active carbacyclin have been disclosed, for example, in "Tetrahedron", Vol. 37, 4391 (1981), "Journal of Organic Chemistry", Vol. 44, 2880 (1979) and "Journal of Organic Chemistry", Vol. 46, 1954 (1981). However, these processes are of the disadvantage of lengthy step. Furthermore, processes for the synthesis of the above-mentioned carbacyclin using as an intermediate (1SR,5RS)-2-ethoxycarbonyl-7,7-ethylenedioxybicyclo[3.3.0]octan-3-one represented by the following formula (VIII) are disclosed, for example, in "Tetrahedron Letters", 3743 (1978), "Journal of Chemical Society, Chemical Communication", 1067 (1978) and "Tetrahedron Letters", 433 (1979). ##STR3## However, the products obtained by the above-mentioned processes are racemic compounds, i.e., the (1SR,5RS) epimers which do not exhibit optical activity. That is, since the intermediates used in these processes are racemic compounds, the products obtained thereby are necessarily racemic compounds. Accordingly, if the optically active (1S,5R) compound can be used as the intermediate in the above-mentioned processes, it follows that the optically active carbacyclin referred to above is obtained quite conveniently.
It has been known in this connection that the above-mentioned intermediate, the compound of the following formula (VIII) is prepared from cis-bicyclo[3.3.0]octane-3,7-dione of the following formula (V) according to the following scheme as taught in the above-mentioned "Journal of Chemical Society, Chemical Communication", 1067 (1978) and "Tetrahedron Letters", 433 (1979). ##STR4##
As can be seen from the above scheme, the compound of the formula (VIII) which is formed by introduction of an ethoxycarbonyl group into the compound of the formula (VII) always becomes a racemic compound which does not have optical activity.
Under such circumstances, we have proposed in Japanese Patent LOP Publn. No. 280294/1986 as a method of isolating only the (1S,5R)epimer from the racemic compound of formula (VIII) a process wherein said racemic compound, (1SR,5RS)-2-ethoxycarbonyl-7,7-ethylenedioxy-bicyclo[3.3.0]-octa n-3-one is treated with a microorganism having an ability of specifically reducing the keto group of the (1R,5S)epimer of the racemic compound (VIII) to afford, as a non-reduced compound, optically active (1S,5R)-2-ethoxy-carbonyl-7,7-ethylenedioxybicyclo[3.3.0]octan-3-one of formula (IV) ##STR5##
The optically active (1S,5R)-2-ethoxycarbonyl-7,7-ethylenedioxybicyclo[3.3.0]octan-3-one of formula (IV) as prepared above can be allowed to lead to an optically active carbacyclin according to the following reaction scheme. ##STR6##
The optical purity of optically active (1S,5R)-2-ethoxycarbonyl-7,7-ethylenedioxybicyclo[3.3.0]octan-3-one of formula (IV) which is prepared by treating (1SR,5RS)-2-ethoxycarbonyl-7,7-ethylenedioxybicyclo[3.3.0]octan-3-one of formula (VIII) with the microorganism according to our previously proposed method may be varied depending on kinds of the microorganism used, but is 92 to 94% e.e. (enantiomer excess) with the best result using Saccharomyces bailii, and the optical purity of the end product, carbacyclin [compound of formula (XVI)]prepared by using the compound of formula (IV) as obtained above is approximately 96% e.e. Where. baker's yeast is used which is inexpensive and most easily available as a microorganism, the optical purity of the resultant compound (IV) is about 60% e.e. and that of carbacyclin obtained with this compound (IV) is still not satisfactory.
On one hand, the intermediates produced in the reaction route starting from the compound of formula (IV) and leading to carbacyclin of formula (XVII) are respectively poor in crystallinity which does not permit the improvement in the optical purity by means of recrystallization. In this situation, a starting material having high optical purity has been needed for the synthesis of carbacyclin.